1-169464035-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BA1

The NM_006996.3(SLC19A2):c.*1814G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 152,418 control chromosomes in the GnomAD database, including 367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.061 (367 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (0 hom.)
• Consequence: SLC19A2 NM_006996.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.42

Genes affected

SLC19A2 (HGNC:10938): (solute carrier family 19 member 2) This gene encodes the thiamin transporter protein. Mutations in this gene cause thiamin-responsive megaloblastic anemia syndrome (TRMA), which is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anemia and sensorineural deafness. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.12).
• BP6: Variant 1-169464035-C-T is Benign according to our data. Variant chr1-169464035-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 293507.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC19A2	NM_006996.3	c.*1814G>A		3_prime_UTR_variant	6/6	ENST00000236137.10
SLC19A2	NM_001319667.1	c.*1814G>A		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC19A2	ENST00000236137.10	c.*1814G>A		3_prime_UTR_variant	6/6	1	NM_006996.3	P1
SLC19A2	ENST00000367804.4	c.*1814G>A		3_prime_UTR_variant	5/5	1
SLC19A2	ENST00000643377.1	n.3030G>A		non_coding_transcript_exon_variant	2/2
SLC19A2	ENST00000646596.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0611 AC: 9282 AN: 151868 Hom.: 366 Cov.: 32

Gnomad AFR AF: 0.0944

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0530

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0787

Gnomad FIN AF: 0.00485

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0432

Gnomad OTH AF: 0.0589

GnomAD4 exome AF: 0.00231 AC: 1 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.00385 AC XY: 1 AN XY: 260

Gnomad4 FIN exome AF: 0.00235

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0611 AC: 9291 AN: 151986 Hom.: 367 Cov.: 32 AF XY: 0.0607 AC XY: 4507 AN XY: 74298

Gnomad4 AFR AF: 0.0944

Gnomad4 AMR AF: 0.0528

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.0789

Gnomad4 FIN AF: 0.00485

Gnomad4 NFE AF: 0.0432

Gnomad4 OTH AF: 0.0601

Alfa AF: 0.0503 Hom.: 61

Bravo AF: 0.0660

Asia WGS AF: 0.0960 AC: 334 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Thiamine-responsive megaloblastic anemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.12
Cadd	Benign	11
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12091844; hg19: chr1-169433273; COSMIC: COSV52548547; COSMIC: COSV52548547;